N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[(2S)-2,3-dihydroxy-propyl]cyclopropanesulfonamide (hereinafter referred to as “(S)-14”, “BAY 86-9766” or “RDEA 119”) is a highly potent and selective MEK1/2 inhibitor currently under development in clinical trials for treatment of late stage cancer patients refractory or intolerant to other anticancer therapies [ref. 1].
The initial synthesis of (S)-14, shown in Scheme A, infra, published in US 2008/0058340 [ref. 2] comprises an osmium catalyzed dihydroxylation of the allyl sulfonamide substituted core followed by chromatographic separation of the enantiomers using a chiral stationary phase: the initial synthesis of (S)-14 provides the target compound as a racemic mixture that needs to be separated by chiral chromatography [ref. 2].

In Scheme A, supra, a racemic mixture of the (S)- and (R)-enantiomers of N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[2,3-dihydroxy-propyl]cyclopropanesulfonamide is produced which, as seen, must be separated by chiral chromatography, in order to provide the single enantiomers. This separation of the enantiomers by chiral chromatography after the last step of the synthesis is a significant drawback in that in addition to the chiral separation step, more than double amounts of all intermediates have to be produced to obtain the same quantity of (S)-14 (RDEA 119).
As mentioned supra, another drawback of prior art synthesis of Scheme A is the use of very toxic osmium tetroxide which requires additional effort to remove the content of osmium to acceptable levels.
Another synthesis of (S)-14, shown in Scheme B, infra, published in PCT patent application under WO 2011/009541 A1 [ref. 7], describes a chiral preparation of (R)— and (S)—N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[2,3-dihydroxy-propyl]cyclopropanesulfonamide and protected derivatives thereof.
Scheme B, infra, illustrates the synthesis of (R)—N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide according to WO 2011/009541 A1 [ref. 7]:

The synthesis as described in WO 2011/009541 A1 starts from commercially available glycidol which is converted via protection of the alcohol and coupling (Step A) with a protected acetylene followed by deprotection (Step B) and iodination with 9-I-BBN (Step C) to provide 4-iodopent-4-ene-1,2-diol, both HO groups of which are protected (Step D). A cyclopropyl group is introduced across the alkene of diol-protected 4-iodopent-4-ene-1,2-diol (Step E) to form the protected 3-(1-iodocyclopropyl)propane-1,2-diol derivative, which is then deprotected (Step F) and protected again (Step G), before the iodo group of which is transformed into a sulfonyl chloride group in Step H.
It has been discovered, and this provides the basis of the present invention, that (S)-14 can be synthesised via a chiral synthesis of sodium 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonate (hereinafter referred to also as compound “(S)-7”) starting from (S)-epichlorohydrin (hereinafter is also referenced as compound “(S)-1”) and alternatively from enantiomerically pure glycidol derivatives, as illustrated in Schemes 1 and 2, infra.
The R-enantiomers have been prepared in the same manner.
Scheme 1, infra, represents a general illustration of the steps used in the chiral synthesis of sodium 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonate ((S)-7) according to the present invention:

It is seen that the steps in Scheme 1 relate to the enantioselective synthesis of (S)-7, using the (S)-enantiomers of all the intermediates involved in said synthesis: as is understood by the person skilled in the art, the enantioselective synthesis of (R)-7 is identical to the synthesis of (S)-7 as illustrated in Scheme 1, supra, except that it uses the (R)-enantiomers of all the intermediates instead of the (S)-enantiomers.
Starting from economically priced chiral epoxypropane derivatives, chiral sodium 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonate ((S)-7) was prepared (Scheme 1, supra), which was converted to chiral 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropane sulfonyl chloride (S)-10, which, in turn, was converted to the final product, N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[(2S)-2,3-dihydroxy-propyl]cyclopropanesulfonamide (S)-14), according to Scheme 2, infra.
Scheme 2, infra, represents a general illustration of the steps used in the chiral synthesis of N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[(2S)-2,3-dihydroxy-propyl]cyclopropanesulfonamide ((S)-14) from sodium 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonate ((S)-7) according to the present invention:

It is seen that the steps in Scheme 2 relate to the enantioselective synthesis of (S)-14, using the (S)-enantiomers of all the intermediates involved in said synthesis: as is understood by the person skilled in the art, the enantioselective synthesis of (R)-14 is identical to the synthesis of (S)-14, except that it uses the (R)-enantiomers of all the intermediates instead of the (S)-enantiomers.
The synthesis of RDEA 119 as depicted in Schemes 1 and 2 of the present invention delivers compound 14 containing 79-85% of the desired enantiomer (S)-14 (via steps A, B, C), hence, only 15-21% of the undesired isomer needs removing via chromatography. The amounts of intermediates and waste as well as the production costs of (S)-14 are thus reduced significantly using the synthesis of the present invention. Further, the use of toxic osmium tetroxide is avoided.
Further, the synthesis of RDEA 119 as depicted in Schemes 1 and 2 of the present invention delivers compound 14 as the desired enantiomer (S)-14 (via steps E, F, G), alleviating the technical problems of the separation of the enantiomers by chiral chromatography, and of the use of toxic osmium tetroxide. The amounts of intermediates and waste as well as the production costs of (S)-14 are thus reduced significantly using the synthesis of the present invention.
The synthesis of the sulfonyl chloride (S-10) depicted in Schemes 1 and 2 according to the present invention involves 5 steps (Steps A, B, C, D and H, or Steps E, F, G, D and H), including one protection step (Step C, starting from (S)-1, or Step G, starting from (S)-8).
Further, the synthesis of the sulfonyl chloride (S-10) depicted in Schemes 1 and 2 according to the present invention proceeds with an overall yield of >60% from (S)-8 (Steps, E, F, G, D, H).
All reagents used in the synthesis of the sulfonyl chloride (S-10) depicted in Schemes 1 and 2 according to the present invention (phosphoryl chloride, dimethoxypropane, sodium methoxide) are cheap and available in bulk.
The synthesis of the sulfonyl chloride (S-10) depicted in Schemes 1 and 2 according to the present invention provides the chiral sodium 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonate (S)-7, as an intermediate, which is a solid which can be purified by crystallization.
As seen in the Experimental section, Example 9b, it was found that the reaction of 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonyl chloride (compound (R)-10) with 5,6-difluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamine (compound 12), in the presence of 4-dimethylaminopyridine in pyridine, provided, under the conditions described, only a percentage yield of 38.9% of N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonamide (compound (R)-13). However, surprisingly, the bromide-promoted method of the present invention as depicted in Scheme 2, Steps J and K) provides the pure (S)-14 product in very good yield: as seen specifically in the Experimental section, Example 9a, it was surprisingly found that the reaction of 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonyl chloride (compound (S)-10) with 5,6-difluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamine (compound 12), in the presence of tetrabutylammonium bromide in pyridine and sulfolane, provided, under the conditions described, a percentage yield of 92.2% of N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonamide (compound (S)-13), thus representing an increase in percentage yield of product of over 50% when directly comparing the method in Example 9a with the method in Example 9b. This is clearly advantageous from a chemical developmental point of view, in view of the productivity of the method and the decrease in the amount of impurities.
Further, more importantly, as seen in the Experimental Section, Example 10a, it was surprisingly found that:                the reaction of 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonyl chloride (compound (S)-10) with 5,6-difluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamine (compound 12), in the presence of tetrabutylammonium bromide in pyridine and sulfolane, then, after complete conversion to N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonamide (compound (S)-13),        followed by stirring the resulting reaction mixture with hydrochloric acid,provided, under the conditions described, a percentage yield of 91.6% of N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[(2S)-2,3-dihydroxy-propyl]cyclopropanesulfonamide (compound (S)-14): this “one-pot” method of Example 10a is clearly advantageous from a chemical developmental point of view, in terms of process efficiency.        
Further, it was surprisingly found that the preparation of (S)-13 from (S)-10-Br and the one pot conversion to R-14 proceeds much cleaner and at a temperature of 23° C., as compared to the preparation of (S)-13 from (S)-10 and the one pot conversion to R-14, which proceeds at a temperature of 70° C.
The method of preparation of (S)-14 from (S)-10 of the present invention, particularly the one-pot method of preparing (S)-14 from (S)-10, as described and defined herein, is thus clearly surprisingly technically advantageous.
The following description provides further general details of each step shown in Schemes 1 and 2, supra, together with the technical advantages thereof.